Neuropeptide Y (NPY), a 36 amino acid peptide, is a sympathetic neurotransmitter and a potent orexigenic factor involved in the regulation of several aspects of neuroendocrine function and behavior, in particular food intake. (Heilig, M. and Widerlov, E., Crit. Rev. Neurobiol., 9:115 (1995)). Five types of NPY receptors, Y1R, Y2R, Y4R, Y5R and Y6R have been characterized. It is thought that NPY exerts orexigenic functions mainly through its receptor subtypes: NPY1R and NPY5R. Several selective antagonists of NPY or its receptors have been developed and tested in vivo as anti-obesity agents. However, clinical trials designed to demonstrate the clinical efficacy of these antagonists in humans did not show clinically meaningful weight loss. For example, the selective NPY5R antagonist MK-0557 (trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6 azaisobenzofuran-1(3H), 1′-cyclohexane]-4′carboxamide) did not induce clinically meaningful weight loss in overweight or obese adults when administered at doses shown to result in receptor saturation (i.e., 1 mg/day, 5 mg/day or 25 mg/day). (Erondu, N. et al., Obesity, 15(4): 895-905 (2007)). Similarly, treatment with MK-0557 following very-low-calorie-diet induced weight loss did not result in a clinically meaningful reduction in weight regain. (Erondu, N. et al., Obesity, 15(4): 895-905 (2007)). Thus, antagonism of NPY5R is not an efficacious strategy for weight loss or control.
In addition to its role in promoting food intake and reducing energy expenditure, NPY has also been implicated in angiogenesis and in the growth of some tumor cells. NPY is present in a highly conserved manner across species, and is involved in several physiological responses and implicated in the pathophysiology of several disorders.
NPY is angiogenic and promotes growth for endothelial, vascular smooth muscle and neuronal cells. The angiogenic activity of NPY is mediated predominantly through NPY1R and NPY2R. NPY5R alone does not mediate angiogenesis, but NPY5R can act as an enhancer to augment angiogenesis mediated through NPY1R and/or NPY2R. (Ruscica, M. et al., Peptides, 28:426-434 (2007); Movafagh, S. et al., FASEB J., 20(11):1924-1926 (2006)). Thus, a selective NPY5R antagonist would not be expected to inhibit angiogenesis or have efficacy in the treatment of an angiogenesis-mediated disease.
NPY and its cognate receptors, Y1R, Y2R and Y5R, are expressed in neural crest-derived tumors, however their role in regulation of tumor growth is unknown. Studies of the effect of NPY and NPY receptor antagonists on the growth and vascularization of neuroendocrine tumors have shown that an NPY5R antagonist blocked the mitogenic effect of NPY and decreased the number of viable SK-N-BE(2) neuroblastoma cells in an in vitro study. In contrast, the same NPY5R antagonist blocked the mitogenic effects of NPY, but increased the number of viable SK-N-MC Ewing's sarcoma cells, and significantly increased the number of viable PC12 pheochromocytoma cells in an in vitro study. (Kitlinska, J. et al., Cancer Res., 65(5):1719-1728 (2005)). These findings demonstrate that the roles of NPY and its receptors in cancer remains to be elucidated.
A need exists to understand the role of NPY5R in cancer and other proliferative diseases, and for methods for treating of such conditions.